Cyclooxygenase-2 (COX2; prostaglandin H2 synthase) and inducible nitric oxide (NO) synthase (iNOS) are two of the principal inflammatory mediators. (1, 2). Following inflammatory stimuli, these two enzymes, which are inactive under basal conditions, undergo new synthesis, respectively manufacturing large quantities of prostaglandins and NO. Needleman and associates had shown that NOS inhibitors can prevent the formation of prostaglandins (Salvemini et al., PNAS 90:7240, 1993). The simplest interpretation of these findings would be that NO, a free radical, gives rise to even more toxic free radicals such as peroxynitrite and hydroxide free radical, which constitute inflammatory stimuli that would lead to induction of COX2 and formation of prostaglandins.
COX2 inhibitors have attained widespread use as anti-inflammatory agents, though they elicit potentially adverse side effects (1, 3-5), while iNOS inhibitors are not presently employed therapeutically. Inflammatory stimuli elicit new synthesis of iNOS and COX2 proteins with similar time courses suggesting that the two systems may interact (6, 7). Stimulants of iNOS such as bradykinin (8) and lipopolysaccharide (LPS) plus interferon γ (IFNγ), components of endotoxin, also enhance prostaglandin formation (9).
There is a continuing need in the art to develop therapies for reducing disease conditions caused by or exacerbated by inflammation.